Heterobicyclic carboxamides and uses thereof
Provided herein are heterobicyclic cyclopropanecarboxamide and heterobicyclic carboxamide compounds. In particular, provided herein are compounds that affect the function of kinases in a cell, and that are useful as therapeutic agents or with therapeutic agents. The compounds provided herein are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, inflammatory diseases, and diseases characterized by abnormal growth, such as cancers. Also provided herein are compositions comprising heterobicyclic cyclopropanecarboxamide or heterobicyclic carboxamide compounds.
1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halogen, CN, NH 2 , OH, C 1-6 alkyl, C 1-6 haloalkyl, O—(C 1-6 alkyl), O—(C 1-6 haloalkyl), or C 3-6 cycloalkyl;
R 2 is H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is
R 4 is S, —C(H)═C(H)—, or —C(H)═N—;
R 5 is H or halogen;
R 6 is CO or SO 2 ;
R 7 is a bond or CH 2 ;
R 8 is CH 2 , phenyl, or a monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, wherein each heteroatom is, independently, N, O, or S;
R 9 is H, halogen, CN, NH 2 , OH, C 1-6 alkyl, C 1-6 alkyl-CN, C 1-6 haloalkyl, O—(C 1-6 alkyl), O—(C 1-6 haloalkyl), or C 3-6 cycloalkyl; and
n is 0 or 1; or
is H, and R 1-6 and n are as defined above.
2 . A compound as in claim 1 , wherein:
R 1 is H, F, Cl, Br, CN, NH 2 , OH, OCF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl;
R 2 is H, F, or C 1-3 alkyl; or
R 9 is H, F, or C 1-3 alkyl.
3 . A compound as in claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
4 . A compound as in claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
5 . A compound as in claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
6 . A compound as in claim 1 , wherein R 4 is S.
7 . A compound as in claim 1 , wherein R 4 is —C(H)═C(H)—.
8 . A compound as in claim 1 , wherein R 4 is —C(H)═N—.
9 . A compound as in claim 1 , wherein R 6 is CO.
10 . A compound as in claim 1 , wherein R 6 is SO 2 .
11 . A compound as in claim 1 , wherein R 7 is a bond.
12 . A compound as in claim 1 , wherein R 7 is a CH 2 .
13 . A compound as in claim 1 , wherein R 1 is H, Cl or Me, R 5 is H, or R 9 is H.
14 . A compound as in claim 1 , wherein R 8 is phenyl.
15 . A compound as in claim 1 , wherein R 8 is a monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, wherein each heteroatom is, independently, N, O, or S.
16 . A compound as in claim 1 , wherein R 8 is a monocyclic C 3-5 heteroaryl having 1-3 nitrogen atoms.
17 . A compound as in claim 1 , wherein:
R 1 is H, F, Cl, CH 3 , CH 2 OH, CH 2 CH 3 , or CN;
R 4 is S, —C(H)═C(H)—, or —C(H)═N—;
R 5 is H;
R 6 is CO or SO 2 ;
R 7 is a bond or CH 2 ;
R 8 is phenyl, or a monocyclic C 4-5 heteroaryl having 1 or 2 nitrogen atoms;
R 9 is H or F; and
n is 1.
18 . A compound as in claim 1 , wherein:
R 1 is H, F, CN, Cl, or CH 3 ;
R 4 is —C(H)═C(H)— or —C(H)═N—;
R 5 is H; and
n is 0.
19 . A compound as in claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20 . A compound as in claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof,
wherein
n is 1;
R 10 is
R 11 and R 12 are connected by an amide or sulfonamide linkage;
R 12 is
and
R 11 is
or n is 0, R 10 and R 12 are as defined above, and R 11 is
21 . A compound as in claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
22 . A compound as in claim 1 , wherein:
R 1 is H, F, Cl, Br, I, CN, NH 2 , OH, OCF 3 , OCH 2 CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl;
R 2 is H, F, Cl, Br, I, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is
R 4 is S, —C(H)═C(H)—, or —C(H)═N—;
R 5 is H, F, Cl, Br, or I;
R 6 is CO or SO 2 ;
R 7 is a bond or CH 2 ;
R 8 is phenyl, or a monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, wherein each heteroatom is, independently, N, O, or S;
R 9 is H, F, Cl, Br, I, C 1-6 alkyl, or C 1-6 haloalkyl; and
n is 0 or 1.
23 . A compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halogen, CN, NH 2 , OH, C 1-6 alkyl, C 1-6 haloalkyl, O—(C 1-6 alkyl), O—(C 1-6 haloalkyl), or C 3-6 cycloalkyl;
R 2 is H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is
R 13 is CH 2 , CH 2 NH,
R 14 is OH, NH 2 , CN, C 1-3 alkyl, phenyl, phenyl-CH 3 , CH 2 -phenyl, phenyl-(O—C 1-6 alkyl), SO 2 —(C 1-6 alkyl), CHCH 2 , C 1-3 alkylene-CN, C 1-6 alkyl-OH, C 1-6 alkyl-NH 2 , a monocyclic C 3-5 heterocycloalkyl having 1-3 heteroatoms, or a monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, wherein each heteroatom is, independently, N, O, or S, and wherein each heteroaryl may be substituted with one or two halogen substituents; and
R 15 is H, CN, OH, or NH 2 .
24 . A compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halogen, CN, NH 2 , OH, C 1-6 alkyl, C 1-6 haloalkyl, O—(C 1-6 alkyl), O—(C 1-6 haloalkyl), or C 3-6 cycloalkyl;
R 2 is H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is
R 16 is phenyl, CH 2 -phenyl, a CH 2 -monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, or a monocyclic C 3-5 heteroaryl having 1-3 heteroatoms, wherein each heteroatom is, independently, N, O, or S, and wherein each heteroaryl may be substituted with one or two halogen substituents;
R 17 is H, OH, halogen, C 1-6 alkyl-OH, C 1-6 alkyl-O—C(O)-phenyl-(R 18 ) z ;
R 18 is H, OH, halogen, or C 1-6 alkyl;
R 19 is H or C 1-6 alkyl;
R 20 is H or C 1-6 alkyl;
z is 0, 1, 2, 3, 4, or 5; and
m is 0, 1, or 2.
25 . A compound, selected from
or a pharmaceutically acceptable salt thereof.
26 . A method of treating glaucoma in a subject in need thereof, comprising administering to the subject a compound as in claim 1 .
27 . A method of treating glaucoma in a subject in need thereof, comprising administering to the subject a compound as in claim 19 .
28 . A method of treating glaucoma in a subject in need thereof, comprising administering to the subject a compound as in claim 23 .
29 . A method of treating glaucoma in a subject in need thereof, comprising administering to the subject a compound as in claim 24 .
30 . A method of treating glaucoma in a subject in need thereof, comprising administering to the subject a compound as in claim 25 .
31 . A method as in claim 26 , wherein the administering is topically to an eye of the subject.
32 . A method as in claim 27 , wherein the administering is topically to an eye of the subject.
33 . A method as in claim 28 , wherein the administering is topically to an eye of the subject.
34 . A method as in claim 29 , wherein the administering is topically to an eye of the subject.
35 . A method as in claim 30 , wherein the administering is topically to an eye of the subject.
36 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound as in claim 1 .
37 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound as in claim 19 .
38 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound as in claim 23 .
39 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound as in claim 24 .
40 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound as in claim 25 .
41 . A method as in claim 36 , wherein the administering is topically to an eye of the subject.
42 . A method as in claim 37 , wherein the administering is topically to an eye of the subject.
43 . A method as in claim 38 , wherein the administering is topically to an eye of the subject.
44 . A method as in claim 39 , wherein the administering is topically to an eye of the subject.
45 . A method as in claim 40 , wherein the administering is topically to an eye of the subject.